In the prior art, liquids collected from organisms and the like have been analyzed by known methods using analyzing devices in which liquid channels are formed. Such analyzing devices can control fluids by using rotators. Further, such analyzing devices can dilute sample liquids, measure solutions, separate solid components, transfer/distribute separated fluids, and mix solutions and reagents by using centrifugal forces, thereby enabling various biochemical analyses.
In an analyzing device for transferring a solution by using a centrifugal force according to Patent Document 1, as shown in FIG. 59A, a sample liquid is collected from an inlet 55 to fill a first cavity 56 by capillarity and then the sample liquid in the first cavity 56 is transferred to a separating cavity 58 by rotating an analyzing device 54 about an axis 57. After that, as shown in FIG. 59B, the sample liquid is centrifugally separated into a plasma component 59a and a blood cell component 59b. The plasma component 59a in the separating cavity 58 is drawn into a cavity 62 through a capillary cavity 61 connected to one end of a capillary channel 60, and a mixture obtained by mixing the plasma component 59a with a reagent retained in the cavity 62 is analyzed by a photometer.
Patent Document 2, Patent Document 3, and Patent Document 4 describe analyzing methods for measuring samples by using centrifugal forces.
FIG. 60 shows the technique of Patent Document 2.
Provided from the center to the outer edge of an analyzing device are a central storage portion 143 for storing a liquid to be diluted before analysis, a measuring chamber 144, an overflow chamber 145, a mixing chamber 146, and measurement cells 147. The measuring chamber 144 is disposed substantially in parallel with the overflow chamber 145, and an opening 150 is provided on the wall surface of the measuring chamber in addition to a feed port 148 and an overflow port 149 so as to be opposed to the feed port 148. The opening 150 is always opened and has a cross section much smaller than those of the feed port 148 and the overflow port 149.
This configuration makes it possible to fill the measuring chamber 144 at high speeds and quickly remove an overflow. When the measuring chamber 144 is filled with a liquid, the liquid immediately starts flowing out of the chamber. Thus it is possible to reduce a ratio of a “feed time” to an outflow time of an “outlet”, the ratio being a function of a ratio of an “inlet sectional area” to an “outlet sectional area”. Hence, accurate measurement can be achieved.
FIG. 61 shows the technique of Patent Document 3.
This analyzing device has a fluid chamber 151, a measuring chamber 152 that is connected to the fluid chamber 151 and is disposed outside the fluid chamber 151 in the radial direction, an overflow chamber 153 connected to the measuring chamber 152, a receiving chamber 154 disposed outside the measuring chamber 152 in the radial direction, and a capillary connecting device 155 for supplying a liquid from the measuring chamber 152 to the receiving chamber 154. The capillary connecting device 155 has a siphon 156 having a capillary structure. The elbowed portion of the siphon 156 is positioned at substantially the same distance from the center of the analyzing device as the innermost point of the measuring chamber 152 in the radial direction, so that a capillary force is smaller than a centrifugal force during a rotation of the analyzing device. For this reason, the interface of liquid/air has the same axis as the analyzing device, the measuring chamber 152 is filled according to the shape of a rotating cylinder having a radius as long as the distance from the center of the analyzing device to the innermost point of the measuring chamber 152 in the radius direction, and an excessive fluid flows into the overflow chamber 153. When the analyzing device is stopped, the liquid supplied into the measuring chamber 152 flows into the capillary connecting device 155 by a capillary force. When the analyzing device is rotated again, the siphon starts to discharge the liquid in the measuring chamber 152 to the receiving chamber 154.
FIG. 62 shows the technique of Patent Document 4.
This analyzing device includes a retaining part 157 having the outer side shaped like a fan extending from the inner periphery to the outer periphery, and a blood cell storing part 158. A portion 159 for connecting the blood cell storing part 158 and the retaining part 157 is convexly formed to prevent a blood cell component fed by centrifugal separation from flowing backward to the retaining part 157. Further, a siphon-shaped output channel 160 is connected to a side of the retaining part 157 and is followed by a configuration in which a sample liquid after an operation can be supplied to the subsequent operation region. Initial blood is supplied to the retaining part 157 through an output channel 161, and a blood cell component having a large specific gravity in the supplied blood is stored in the blood cell storing part 158 by a centrifugal force. The number of revolutions of the analyzing device is reduced when the separation is nearly completed, so that a balance between a capillary force that is applied to a solution in the output channel 160 connected to the retaining part 157 and a centrifugal force is reversed and plasma and serum components remaining in the retaining part 157 are discharged to the subsequent operation region through the output channel 160 by centrifugal separation.
In recent years, there have been growing demands in the market for a reduction in the volume of a sample liquid, size reduction of a device, short-time measurement, simultaneous measurement on multiple items, and so on. Thus more accurate analyzers have been demanded to react a sample liquid such as blood with various analytical reagents, detect a mixture of the sample liquid, and inspect the stages of various diseases in a short time.
Generally, in such an analyzing device, a sample liquid is rarely reacted as it is with a reagent and frequently requires pretreatment such as the dilution of the sample liquid with a buffer solution and the like and the removal of fine particles in the sample liquid according to the purpose of analysis. For example, when the sample liquid is diluted, it is necessary to accurately derive a dilution factor in an actual calculation process of a measurement value.
The analyzing device of Patent Document 5 is an example in which pretreatment is performed and a dilution factor is derived optically on the analyzing device.
FIG. 63 shows the analyzing device of Patent Document 5.
A rotor body 202 is substantially formed of a solid disk. FIG. 44 shows a bottom layer 204 of the rotor body 202. An enclosed reagent container 206 is placed in a chamber 208 of the bottom layer 204 and extends from an outlet channel 210 to the inside in the radial direction. A reagent is transferred into a mixing chamber 212 through the outlet channel 210.
The reagent container 206 contains a diluent to be mixed with a biological sample. For example, when the sample is blood, the diluent may be an ordinary saline solution (0.5% saline solution), a phosphoric acid buffer solution, a Ringer lactate solution, and a standard diluent similar to these solutions. The enclosed reagent container 206 is opened in response to the installation of the rotor body 202 in an analyzer. After the opening of the reagent container 206, the reagent in the reagent container 206 flows into the mixing chamber 212 through the outlet channel 210.
The mixing chamber 212 contains a marker mixture that is photometrically detectable and specifies the dilution of the biological sample to be tested.
After the mixing, the diluent flows out of the mixing chamber 212 into a measuring chamber 216 through a siphon 214. The measuring chamber 216 is connected to an overflow chamber 218. The volume of the measuring chamber 216 is smaller than that of the reagent container 206. An excessive volume of the diluent flows into the overflow chamber 218 with a predetermined volume of the diluent remaining in the measuring chamber 216. The excessive volume of the diluent in the overflow chamber 218 flows into a collecting chamber 222 through a passage 220.
Next, for use as a reference value in an optical analysis of the biological sample, the diluent flows outward in the radius direction and flows into system cuvettes 224. The predetermined volume of the diluent in the measuring chamber 216 flows into a separating chamber 228 through a siphon 226 and is mixed with the biological sample to be analyzed, so that the sample is diluted. The sample is supplied into the rotor body 202 through an inlet on a top layer (not shown).
A sample measuring chamber 230 is connected to a sample overflow chamber 232 via a connecting channel 234. The depths of the sample measuring chamber 230 and the overflow chamber 232 are selected to be capillary dimensions. The measured sample then flows into the separating chamber 228. The separating chamber 228 is used for removing cellular materials from a biological sample such as whole blood. The separating chamber 228 is made up of a cell trap 236 formed on the outer periphery relative to the radial direction and a receiving hole region 238 formed along the inner periphery relative to the radial direction. A capillary region (not shown) is formed between the receiving hole region 238 and the cell trap 236 to prevent backflow of a cellular component trapped in the cell trap 236 as a result of centrifugal separation. The volume of the receiving hole region 238 is so large as to receive plasma containing no diluted cellular components. The diluted plasma flows from the separating chamber 228 into a second separating chamber 244 though a siphon 242, and cellular components are further separated in the second separating chamber 244.
Next, the diluted sample flows into a collection chamber 248 through a passage 246 and is transferred to cuvettes 250 to conduct an optical analysis. The cuvettes 250 contain a reagent necessary for the optical analysis of the sample. The dilution factor of the sample can be derived from the optical measurement value only of the diluent obtained by the foregoing technique and the optical measurement value of the diluted sample.
In some methods of the prior art, a biological fluid is electrochemically or optically analyzed using a microchip on which a micro-channel is formed. In an electrochemical analysis method, a biosensor for analyzing specific components in a sample liquid determines a blood sugar level and so on by, for example, measuring a current value obtained by a reaction of glucose in blood and a reagent such as glucose oxidase retained in the sensor.
In an analyzing method using a microchip, a fluid can be controlled using a rotator having a horizontal axis and it is possible to measure a sample liquid, separate cellular materials, transfer/distribute a separated fluid, and mix/stir a liquid by using a centrifugal force, thereby conducting various biochemical analyses.
FIG. 64 shows a centrifugal transfer biosensor 400 illustrated in Patent Document 6 and so on. The centrifugal transfer biosensor 400 can conduct a quantitative analysis simultaneously on multiple sample solutions introduced into a microchip. In this configuration, a sample solution is transferred from an inlet port 409 to an outlet port 410 by a capillary force and fills capillary channels 404a to 404f. After that, a centrifugal force generated by a rotation of the biosensor 400 distributes the sample liquid in the capillary channels through liquid branch points 406a to 406g arranged on the same circumference. Further, the sample liquid passes through small connecting conduits 407a to 407f and is transferred to the subsequent processing chamber (not shown).
Patent Document 1: National Publication of International Patent Application No. 4-504758
Patent Document 2: Japanese Patent Laid-Open No. 61-167469
Patent Document 3: National Publication of International Patent Application No. 5-508709
Patent Document 4: Japanese Patent Laid-Open No. 2005-345160
Patent Document 5: National Publication of International Patent Application No. 7-503794
Patent Document 6: National Publication of International Patent Application No. 2005-502031